(1.08) Iatrogenic Cushing’s Syndrome in the Setting of Decreased Oral Budesonide and Dexamethasone Mouth Rinse Catabolism due to Voriconazole-Mediated CYP3A4 Enzyme Inhibition

Introduction : Few case reports have described the development of iatrogenic Cushing’s in the setting of oral budesonide and dexamethasone mouth rinse formulations with concomitant voriconazole therapy. This abstract describes such a case which resolved with switching from voriconazole to isavuconazonium.

Case(s) Description : A 46-year-old female with history notable for chronic myeloid leukemia status post bone marrow transplant complicated by graft versus host disease (GVHD) on immunosuppressive therapy with invasive aspergillosis presented with 2-month history of lower extremity weakness, falls, weight gain and easy bruising. Medications included oral budesonide initiated 7 months ago for GVHD, Dexamethasone mouth wash initiated 2 months prior for oral mucosal ulcerations, voriconazole, and tacrolimus. Physical exam noted central adiposity and diffuse lower extremity bruising with 3/5 muscle strength bilaterally. Vital signs included an elevated blood pressure of 144/86 mmHg. Laboratory and imaging workup showed normal creatinine kinase, new diagnosis of pre-diabetes with hemoglobin A1C 5.8%. EMG suggested type 2 fiber atrophy consistent with muscle disuse vs drug-induced myopathy. Synthetic glucocorticoid screen was positive for both budesonide and dexamethasone. Serum dexamethasone level was noted to be 303 ng/dl (< 30). 8 AM plasma cortisol was low at 1.4 ug/dl (7-25) with ACTH level < 5 pg/ml (6-65) and DHEA-S level low at 15 mcg/dl (19-231) indicating hypothalamic-pituitary-adrenal (HPA) axis suppression. As systemic side effects of oral budesonide and mouth rinse Dexamethasone are rare, increased systemic absorption due to reduced steroid catabolism from CYP450 enzyme inhibition was suspected. Since patient was treated with high doses of voriconazole, which is potent inhibitor of the CYP450 3A4 enzyme, it was discontinued and switched to isavuconazonium.  Three months later, she was noted to have improved muscle strength and her hemoglobin A1C normalized to 5.4%. A random cortisol level drawn in late afternoon showed improvement to 4.25 ug/dl (7-25) with improvement in her DHEA-S level 58.9 ug/dl (19-231). Her serum Dexamethasone level is now undetectable (< 30 ng/dl) despite continuation of the same dose of Dexamethasone and oral budesonide.

Discussion : CYPA3A4 plays a significant role in steroid hormones catabolism and drug-drug interactions. There are several drugs that inhibit this enzyme, with the azole antifungal class being one of the strongest inhibitors with strong voriconazole-mediated competitive and non-competitive inhibition of hepatic and gut CYP3A4 activity. Budesonide undergoes extensive first-pass hepatic and gut metabolism mediated by CYP450 enzymes with bioavailability of only about 10-15%. Dexamethasone is also metabolized by CYP450 enzymes. In the setting of concomitant voriconazole use leading to inhibited steroid catabolism , this patient systemically absorbed oral budesonide and Dexamethasone at levels high enough to suppress the HPA axis and had iatrogenic Cushing’s syndrome. The symptoms improved after discontinuation of voriconazole.